Statistical Evaluation of Bioequivalence Studies - BEBAC ...

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Acceptance range for C max2. Assessment of C max in bioequivalence studies. In whichcases is it allowed to use a wider acceptance range for theratio of C max ?The NfG states under 3.6.2 that “With respect to the ratio of C maxthe 90% confidence interval for this measure of relative bioavailabilityshould lie within an acceptance range of 0.80 – 1.25. In specificcases, such as a narrow therapeutic range, the acceptanceinterval may need to be tightened.”The NfG also states that “In certain cases a wider interval may beacceptable. The interval must be prospectively defined, e.g. 0.75 –1.33, and justified addressing in particular any safety or efficacyconcerns for patients switched between formulations”.Anonymous [EMEA/CHMP/EWP/40326/2006];Questions & Answers on the BA and BE Guideline (27 July 2006)Dissolution Testing, Bioavailability & Bioequivalence | Budapest, 24 May 2007 16
Acceptance range for C maxThe possibility offered here by the guideline to widen the acceptancerange of 0.80 – 1.25 for the ratio of C max (not for AUC) shouldbe considered exceptional and limited to a small widening (0.75 −1.33).Restricted to products for which at least one of the following criteriaapplies:1) Data on PK/PD relationships (safety and efficacy) adequate todemonstrate that PD is not affected in a clinically significant way.2) If PK/PD data are inconclusive or not available, clinical safety andefficacy data may be used, but specific for the compound andpersuasive.3) Reference product is a HVDP. See #8 of the Q&A document.Comment: In a silent side-step widening of the acceptance rangefor AUC (NfG: „AUC-ratio: […] In rare cases a wider acceptancerange may be acceptable if it is based on sound clinical justification.“)was entirely eliminated.Dissolution Testing, Bioavailability & Bioequivalence | Budapest, 24 May 2007 17
Page 1: Statistical Evaluation ofBioequival
Page 7: Assumptions: StatisticsMultiplicati
Page 12: Nonparametrics5. In which cases may
Page 18 and 19: Outliers• Problems• Parametric
Page 20 and 21: Outliers• Solution II• Stay wit
Page 22 and 23: Re-testing of subjectsn=24: 83.3%-1
Page 24 and 25: Add-on Design• Reasonable,• if
Page 26 and 27: Group Sequential Design± EU• Per
Page 29 and 30: Studiesof >2 formulations• Disadv
Page 31 and 32: Studiesof >2 formulations• Often
Page 33: Parallel Groups• Design Issues•
Page 36 and 37: Parallel Groups: Example• Evaluat
Page 38 and 39: Parallel Groups: Example• Evaluat
Page 40 and 41: Sample Size• Minimum Number of Su
Page 42 and 43: Sample Size: Planning• NfG on the
Page 48 and 49: Sample Size: PlanningDoxicycline (3
Page 50 and 51: Sample Size: PowerPower to show BEw
Page 53: Sample Size: Sensitivity Analysis
Page 58: Low Variability• Drugs / Drug Pro
Page 63 and 64: Nuisance: sequence effect• In a
Page 65 and 66: Nuisance: sequence effect• In a l
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Nuisance: sequence effect• Conclu
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Are we making progress?• About 3
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...to be rememberedWhenever a theor
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Statistical Evaluation ofBioequival
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